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To evaluate the quality of whole-exome sequencing (WES) reporting in the epilepsy literature. We aimed to assess the quality of reporting of WES in epilepsy. We compared studies based on journal type and if outcome reporting biases exist. We used a self-constructed benchmark to quantitatively analyze studies. We included 451 publications. Reporting was heterogeneous with poor reporting of (1) ACMG guideline application 13% and (2) Human Phenotype Ontology (HPO) numbers in 3% of studies, 3) VUS in 19%. Predictors of reporting included journal type and journal impact factor. Date of publication and publication type were not predictors of poor reporting. Pairwise comparisons of genetics versus neurology journals using relative risks yielded significant differences in reporting of ACMG guideline application (RR 1.88, 95% CI 1.04-3.38); HPO numbers (RR 8.62, 95% CI 1.08-63.37) and deposition of findings to ClinVar (RR 2.50, 95% CI 1.03-6.1). Reporting of WES literature is heterogeneous in quality, and poor reporting hinders collaboration and accession of data into large databases like OMIM and OrphaNet. This study highlights reporting bias in this area and, formal structural guidelines like the CONSORT guidelines used in the reporting of clinical trials are needed to address the issue.

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (

Background Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. Methods Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. Results Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis. Conclusions These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.

Topical povidone-iodine (PVP-I) is currently being considered as a potential preventive measure against the spread of COVID-19. Diluted PVP-I solutions have been historically used in Asia to treat upper respiratory tract infections (URTIs) by decreasing the bacterial and viral load on oropharyngeal mucosa to decrease the transmission of diseases. Efficacy of gargling 0.23% PVP-I mouthwash in Japan demonstrated to be efficacious in lowering the prevalence of URTIs when compared with placebo. The 0.23% concentration was used in vitro on severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, which produced undetectable traces after 30 seconds of exposure. Additionally, a recent study in 2020 proved the efficacy of PVP-I 0.45%10% in reducing COVID-19 (SARS-CoV 2) viral load in vitro. Numerous clinical trials are being conducted to determine if there is a decrease in viral load, and thus transmission, when using oral or nasal topical PVP-I in COVID-19 patients. Because of the current lack of evidence for the use of PVP-I in vivo with COVID-19, it is recommended to await the clinical trial results before initiating this practice.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71–83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

Biliary tract cancers (BTC) arise from biliary epithelium and include cholangiocarcinomas or CCA (including intrahepatic (ICC) and extrahepatic (ECC)) and gallbladder cancers (GBC). They often have poor outcomes owing to limited treatment options, advanced presentations, frequent recurrence, and poor response to available systemic therapy. Mucin 5AC (MUC5AC) is rarely expressed in normal biliary epithelium, but can be upregulated in tissues of benign biliary disease, premalignant conditions (e.g., biliary intraepithelial neoplasia), and BTCs. This mucin’s numerous glycoforms can be divided into less-glycosylated immature and heavily-glycosylated mature forms. Reported MUC5AC tissue expression in BTC varies widely, with some associations based on cancer location (e.g., perihilar vs. peripheral ICC). Study methods were variable regarding cancer subtypes, expression positivity thresholds, and MUC5AC glycoforms. MUC5AC can be detected in serum of BTC patients at high concentrations. The hesitancy in developing MUC5AC into a clinically useful biomarker in BTC management is due to variable evidence on the diagnostic and prognostic value. Concrete conclusions on tissue MUC5AC are difficult, but serum detection might be relevant for diagnosis and is associated with poor prognosis. Future studies are needed to further the understanding of the potential clinical value of MUC5AC in BTC, especially regarding predictive and therapeutic value.

Background and aims Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. Methods In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. Results Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P Conclusions A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients. Graphical abstract

Objectives: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease.Methods: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system.Results: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management.Significance: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.

Termatiko sets are combinatorial structures that have been shown to hinder the success of the Interval-Passing Algorithm in compressed sensing. In this paper, we show how termatiko sets relate to other combinatorial structures in graphs representing measurement matrices that are also known to cause failure in similar iterative algorithms. We give bounds on the sizes of termatiko sets of measurement matrices based on finite geometries and also investigate the effect of the redundancy of the matrices on the number of these sets.

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.

A power dominating set of a graph G is a set S of vertices that can observe the entire graph under the rules that (1) the closed neighborhood of every vertex in S is observed, and (2) if a vertex and all but one of its neighbors are observed, then the remaining neighbor is observed; the second rule is applied iteratively. The power domination number of G , denoted by γ P ( G ) , is the minimum number of vertices in a power dominating set. A Nordhaus–Gaddum problem for power domination is to determine a tight lower or upper bound on γ P ( G ) + γ P ( G ¯ ) or γ P ( G ) ⋅ γ P ( G ¯ ) , where G ¯ denotes the complement of G . The upper and lower Nordhaus–Gaddum bounds over all graphs for the power domination number follow from known bounds on the domination number and examples. In this note we improve the upper sum bound for the power domination number substantially for graphs having the property that both the graph and its complement are connected. For these graphs, our bound is tight and is also significantly better than the corresponding bound for the domination number. We also improve the product upper bound for the power domination number for graphs with certain properties.

Background During radiotherapy of left-sided breast cancer, parts of the heart are irradiated, which may lead to late toxicity. We report on the experience of single institution with cardiac-sparing radiotherapy using voluntary deep inspiration breath hold (V-DIBH) and compare its dosimetric outcome with free breathing (FB) technique. Patients and methods Left-sided breast cancer patients, treated at our department with postoperative radiotherapy of breast/chest wall +/– regional lymph nodes between May 2015 and January 2017, were considered for inclusion. FB-computed tomography (CT) was obtained and dose-planning performed. Cases with cardiac V25Gy ≥ 5% or risk factors for heart disease were coached for V-DIBH. Compliant patients were included. They underwent additional CT in V-DIBH for planning, followed by V-DIBH radiotherapy. Dose volume histogram parameters for heart, lung and optimized planning target volume (OPTV) were compared between FB and BH. Treatment setup shifts and systematic and random errors for V-DIBH technique were compared with FB historic control. Results Sixty-three patients were considered for V-DIBH. Nine (14.3%) were non-compliant at coaching, leaving 54 cases for analysis. When compared with FB, V-DIBH resulted in a significant reduction of mean cardiac dose from 6.1 +/– 2.5 to 3.2 +/– 1.4 Gy (p < 0.001), maximum cardiac dose from 51.1 +/– 1.4 to 48.5 +/– 6.8 Gy (p = 0.005) and cardiac V25Gy from 8.5 +/– 4.2 to 3.2 +/– 2.5% (p < 0.001). Heart volumes receiving low (10–20 Gy) and high (30–50 Gy) doses were also significantly reduced. Mean dose to the left anterior coronary artery was 23.0 (+/– 6.7) Gy and 14.8 (+/– 7.6) Gy on FB and V-DIBH, respectively (p < 0.001). Differences between FB- and V-DIBH-derived mean lung dose (11.3 +/– 3.2 vs. 10.6 +/– 2.6 Gy), lung V20Gy (20.5 +/– 7 vs. 19.5 +/– 5.1 Gy) and V95% for the OPTV (95.6 +/– 4.1 vs. 95.2 +/– 6.3%) were non-significant. V-DIBH-derived mean shifts for initial patient setup were ≤ 2.7 mm. Random and systematic errors were ≤ 2.1 mm. These results did not differ significantly from historic FB controls. Conclusions When compared with FB, V-DIBH demonstrated high setup accuracy and enabled significant reduction of cardiac doses without compromising the target volume coverage. Differences in lung doses were non-significant.

Introduction: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD. publishersversion published

Background: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment. Methods: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared. Results: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39). Conclusions: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.

INTRODUCTION Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure. METHODS Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non-ADTKD renal transplant recipients. RESULTS We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite-ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow-up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty-five transplant biopsies were performed during follow-up, and none of these showed signs of recurrent ADTKD post-transplant. CONCLUSION In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.

Radio labeling of graphs is a specific type of graph labeling. The basic type of graph labeling is vertex coloring; this is where the vertices of a graph G are assigned different colors so that adjacent vertices are not given the same color. A k-coloring of a graph G is a coloring that uses k colors. The chromatic number of a graph G is the minimum value for k such that a k-coloring exists for G [2]. Radio labeling is a type of graph labeling that evolved as a way to use graph theory to try to solve the channel assignment problem: how to assign radio channels to radio transmitters so that two transmitters that are relatively close to one another do not have frequencies that cause interference between them. This problem of channel assignment was first put into a graph theoretic context by Hale [6]. In terms of graph theory, the vertices of a graph represent the locations of the radio transmitters, or radio stations, with the labels of the vertices corresponding to channels or frequencies assigned to the stations. Different restrictions on labelings of graphs have been studied to address the channel assignment problem. Radio labeling of a simple connected graph G is a labeling f : V (G) → Z such that for every pair of distinct vertices u and v of G, distance(u, v) + |f(u) − f(v)| ≥ diameter(G) + 1. The radio number of G is the smallest number m such that there exists a radio labeling f with f(v) ≤ m for all v in V (G). The radio numbers of certain families of graphs have already been found. Bounds and radio numbers of some tree graphs have been determined. Daphne Der

Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift β(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins.

PURPOSE: New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations.METHODS: Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes.RESULTS: Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals).CONCLUSION: Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.

This exploratory study extended past studies of children's ability to reference the mirror as a tool in locating the source of reflected images to preschoolers' ability to use the affordances of a transparency. Thirty-six children (3.5 to 5 years old) were shown nonreflected lights and lights reflected on a partially transparent, glassy surface. Children did not spontaneously locate the source of the reflected image. However, they were able to verbally discriminate reflected from nonreflected images following training. These findings indicate that, although preschoolers may not spontaneously use transparencies as a perceptual tool, the ability to distinguish visual differences of reflected from nonreflected images on transparencies is likely within preschool children's developmental capacity.

We describe flux tubes and their interactions in a low energy sigma model induced by $SU({N_f}) \rightarrow SO({N_f})$ flavor symmetry breaking in $SO(N_c)$ QCD. Unlike standard QCD, this model allows gauge confinement to manifest itself in the low energy theory, which has unscreened spinor color sources and global $Z_2$ flux tubes. We construct the flux tubes and show how they mediate the confinement of spinor sources. We further examine the flux tubes' quantum stability, spectrum and interactions. We find that flux tubes are Alice strings, despite ambiguities in defining parallel transport. Furthermore, twisted loops of flux tube support skyrmion number, just as gauged Alice strings form loops that support monopole charge. This model, while phenomenologically nonviable, thus affords a perspective on both the dynamics of confinement and on subtleties which arise for global Alice strings., Comment: 29 pages (REVTEX) plus 6 figures, two corrections in the final section and added references

Profound hypercalcemia is usually due to underlying malignancy.We describe a case of granulomatous myositis presenting with extreme hypercalcemia of 20.1 mg/dl and generalized weakness that did not resolve despite rapid correction of serum calcium. The disease process was unmasked by cholecalciferol supplementation. Initial search for a malignant process yielded no diagnosis, but an elevated 1,25-dihydroxyvitamin D level, in the setting of a suppressed PTH and undetectable PTHrP, pointed to the presence of excessive 1α-hydroxylase activity.Biopsy of the vastus lateralis muscle showed extensive granulomatous myositis. Immunohistochemical staining for 1α-hydroxylase was localized to the multinucleated giant cells and histiocytes. Musculoskeletal magnetic resonance imaging showed involvement of proximal muscle groups of both thighs and upper limbs.Measurement of vitamin D metabolites is pivotal in diagnosing 1,25-dihydroxyvitamin D-mediated hypercalcemia. Granulomatous disease can occasionally cause profound hypercalcemia and needs to be considered in the differential diagnosis. 1,25-Dihydroxyvitamin D-mediated hypercalcemia is responsive to glucocorticoid therapy.

Abstract 1022 Beta-thalassemia is caused by β-globin gene mutations that result in either markedly decreased (β+) or absent (β0) β-globin chain production. Patients who are either homozygous or compound heterozygous for β-thalassemia mutations are severely anemic and require chronic RBC transfusions. Concomitant inheritance of an α -thalassemia mutation or increased HbF (α 2γ2) expression can ameliorate the disease severity. Surprisingly, many patients homozygous for the codon 8 (–AA) β0-thalassemia mutation are mildly anemic with over 95% HbF [Altay & Gürgey, Ann NY Acad Sci 612:81, 1990]. We now report one such patient, a 20-year old man of Iraqi ancestry who was found to have splenomegaly but was otherwise well. His hemoglobin was 12.4 g/dL, MCV 77 fL, reticulocyte count 3.2%. Hemoglobin analysis by HPLC revealed HbF 98%, HbA2 2%. Multiplex ligation-dependent probe amplification (MLPA) of his β-globin gene cluster confirmed that he did not have a large deletion as found in some patients with hereditary persistence of fetal hemoglobin (HPFH), nor γ-globin gene quadruplication. In addition, he was heterozygous for the α 2 IVSI donor splice site 5 bp deletion (–GTGAG), the α Hph thalassemia mutation. To determine the genetic basis for his persistently high HbF expression, his γ-globin gene promoters were sequenced and no HPFH point mutation was found. We next assessed the status of his 3 major HbF quantitative trait loci (QTL). He was homozygous for SNP rs7482144 C>T minor allele (Xmn I polymorphism) at 158 bp 5' to the Gγ-globin gene on chr 11p15; homozygous for rs9399137 minor allele in the HBSIL-MYB intergenic polymorphism (HMIP) on chr 6q23, homozygous for the 3-bp deletion which is in linkage disequilibrium with rs9399137 minor allele [Farrell et al, Blood 117:4935, 2011]; and heterozygous for rs766432 minor allele in the 2nd intron of BCL11A on chr 2p16. Thus he had alleles associated with elevated HbF in all 3 QTL. No mutation was found in his KLF1 genes. Within HS2 in his β LCR is the motif (TA)9 (CA)2 (TA)2 CG (TA)10 which is found in Senegal β-globin haplotype 3 [Öner et al, Blood 79:813, 1992]. The Corfu deletion removes part of the δ-globin gene and ∼6 kb upstream flanking sequence, encompassing the 2-kb region reported to be necessary for γ-globin gene silencing [Sankaran et al, NEJM 365:807, 2011], and is often in LD with the IVSI-5 G>A severe β+-thalassemia mutation. Corfu heterozygotes have slightly increased HbF, but Corfu homozygotes have HbF ∼95%. We sequenced 6.5 kb upstream of δ-globin gene in our patient, and found homozygosity throughout and only 2 nucleotide differences from the GRCh37/hg19 assembly sequence: C>T (rs3759074) at 2,065 bp, and T>G (rs7948416) at 718 bp upstream of δ globin gene transcription start site. No deletion was found. At the repressor protein BP1 binding site 530 bp upstream of the β-globin gene, our patient had the common reference sequence, (AC)2 (AT)7 T7. Among 13 subjects heterozygous for codon 8 (–AA) β0-thalassemia mutation, their Hb was 11.6 ± 1.8 g/dL, HbF 2.8 ± 2.6% [Öner et al, Hemoglobin 14:1, 1990]. We studied two unrelated codon 8 (–AA) heterozygotes. One was a 37-year old woman with Hb 9.8, HbA 88%, HbF 5.7%. She was homozygous for the Xmn I polymorphism, and heterozygous for the HbF QTL on chr 6q23 and 2p16. The other was a 24-year old woman with Hb 11.2, HbA 90%, HbF 7.5%. She was homozygous for the Xmn I polymorphism, and heterozygous for the HbF QTL on chr 2p16. These results support the hypothesis that determinant(s) in cis to the β-globin gene cluster, including the Xmn I QTL and related functional motif(s), in concert with HMIP and BCL11A QTL can sustain high-level γ-globin gene transcription in adults. Robust γ-mRNA accumulation and HbF expression occur only when β-mRNA is markedly decreased due to nonsense mediated decay in the codon 8 (–AA) homozygote, as has been shown in patients homozygous for the Corfu deletion [Chakalova et al, Blood 105:2154, 2005] and in experimental model system [Russell, Eur J Haematol 79:516, 2007]. Our findings could have implications for the therapeutic design to induce HbF expression in β-hemoglobinopathies. Disclosures: No relevant conflicts of interest to declare.

Three aspects of socio-historical context were discussed with respect to their impact on vivid memories and reminiscence. The first aspect related to ageism. One possible explanation for the reminiscence phenomenon is that older adults recall their youth preferentially because of the higher valuation of youth over the old in the U.S. We found previously that older adults in Japan showed fewer youthful reminiscences than U.S. seniors did, perhaps because of the greater respect for the old there than in the U.S. The Japanese recalled their twenties most frequently while the Americans recalled their teens. Their twenties corresponded to the years during World War II for most of the people sampled in the study, and many memories were war-related. These data were reanalyzed with all war-related memories removed and the effect held: the average age of memories was older for the Japanese than the U.S. subjects, which is consistent with an ageism hypothesis, but not conclusive support for it. A second aspect of socio-historical context concerned the enduring psychological impacts of major historical events. The influence of World War II on the autobiographical memories of the Japanese was discussed. In addition, a third aspect of socio-historical context was discussed: we found urban vs. rural differences in midwestern U.S. adults in the content of autobiographical memories as categorized canonically. One implication of all three findings was that socio-historical and developmental factors interact in producing the reminiscence phenomenon.

In her article "An Analysis of University Definitions of Sexual Harassment" (Signs 8, no. 4 [Summer 1983]: 696-707), Phyllis L. Crocker evaluates the definitions of sexual harassment used by academic, professional, and governmental bodies. Her analysis is astute, enlightening, and important. However, she makes no mention of sexual harassment of women professors by their men students.' There is a general lack of awareness of this type of harassment not only in Crocker's work and the official definitions but also in other research on sexual harassment within